This award will provide an opportunity for the Principal Investigator (PI) to develop as an independent patient-oriented scientific investigator in the field of human genome epidemiology. By pursuing didactic course work in genetic epidemiology and acquiring skills in molecular genetic laboratory techniques, the PI will become a properly trained genetic epidemiologist with an in-depth understanding of the technical aspects of molecular genetics. This will ultimately lead to a successful independent research career focused upon understanding the genetic determinants of pathogen recognition, the host immune response, and the clinical diseases associated with exposure to invading pathogens and their products. The primary scientific goal of this proposal is to determine the association between the toll-like receptor 4 (TLR4) polymorphisms and gram-negative (GN) bacteremia. Aim I will use samples from a genetic repository derived from stem cell transplant patients and donors. A case-control study will identify any potential association between the null TLR4 alleles and acquiring GN bacteremia. This study will also provide a unique insight into gene environment and gene-gene interaction with the tumor necrosis factor-alpha (TNF-cc) polymorphisms. In addition, we will examine whether the TLR4 alleles effect the host immune response, measured clinically by acute physiology scores. Aim 2 will be a prospective family-based genetic study lasting the duration of this funding period. Initial laboratory studies will focus on development of an ex vivo lipopolysaccharide (LPS) hyporesponsive phenotype through the use of whole blood culture assays. The phenotype will be identified for each hematopoietic stem cell or bone marrow transplant patient. Genetic information from the patient, parents, and siblings, will then be used in a transmission disequilibrium test to determine whether the TLR4 polymorphisms are associated and genetically linked to the ex vivo LPS hyporesponsive phenotype. Ultimately, this cohort of patients will be developed in anticipation of future genetic discoveries in the complicated pathway of pathogen recognition and host inflammatory response.